ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.58C>T (p.Gln20Ter)

dbSNP: rs1567786905
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000698970 SCV000827661 pathogenic Neurofibromatosis, type 1 2024-04-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln20*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 18546366). ClinVar contains an entry for this variant (Variation ID: 576465). Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000698970 SCV001479160 likely pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000698970 SCV002561540 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002352176 SCV002652564 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-12-20 criteria provided, single submitter clinical testing The p.Q20* pathogenic mutation (also known as c.58C>T), located in coding exon 1 of the NF1 gene, results from a C to T substitution at nucleotide position 58. This changes the amino acid from a glutamine to a stop codon within coding exon 1. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This alteration has been reported in patients with either clinical diagnosis of or suspicion of Neurofibromatosis type 1 and RNA studies have demonstrated that this alteration results in a deletion of the last 4 nucleotides in exon 1 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV004702342 SCV005202022 pathogenic not provided 2024-12-05 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: deletion of the last 4 nucleotides in exon 1 due to the creation of an aberrant splice site, leading to a frameshift that is expected to result in protein truncation or nonsense mediated decay (PMID: 18546366); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29673180, 37453313, 23913538, 36612057, 18546366)

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